The present invention relates to methods for the preparation of N-unsubstituted 2-azetidinones, and to novel compounds useful in said methods.
Taxol, a compound isolated from the bark of Pacific yew trees, has recently emerged as a promising anticancer drug, particularly in the treatment of ovarian cancer. Because taxol is only present in small quantity in the bark of the slow-growing Pacific yew, there is a continuing interest in a practical synthetic or semi-synthetic route to taxol in order to meet the increasing demand for the drug without unduly burdening the Pacific yew population.
U.S. Pat. No. 5,175,315 issued to R. A. Holton on Dec. 29, 1992 discloses the coupling of protected baccatin III with protected N-benzoyl-3-hydroxy-4phenyl-2-azetidinone (A) to give taxol. ##STR1##
In U.S. Pat. No. 5,175,315 it is disclosed that 3-acetoxy-4-phenyl-2-azetidinone (B), a precursor to (A), is prepared by reacting acetoxyacetyl chloride with N-benzylidene-4-ethoxyaniline to give N-(4-methoxyphenyl)-3-acetoxy4-phenyl-2-azetidinone, followed by removal of the 4-methoxyphenyl group with cerium ammonium nitrate (CAN). This process is also applicable to the synthesis of 2-azetidinones with other 3- and 4-substituents. ##STR2## The above process for the preparation of .beta.-lactam (B) requires the use of large quantity of CAN, rendering it impractical as a large scale manufacturing process. Therefore, there is the need for an improved process for the preparation of 3,4-disubstituted-2-azetidinones that is amenable to scale-up production.
Manhas et al, in "Cyanuric Chloride: A Mild Reagent for .beta.-Lactam Synthesis" Synthesis, 1981, 209-211, reports the synthesis of 3-azido-4-phenyl-2-azetidinone from potassium azidoacetate, hydrobenzamide and cyanuric acid in the presence of triethylamine, followed by treatment with 10% HCl. Wells and Lee in "The Synthesis of 2-Azetidinones" J. Org. Chem., 1969, 34:1477-1479 reports the synthesis of 3-azido4-phenyl (and substituted phenyl) -2-azetidinone from azidoacetyl chloride and hydrobenzamide in the presence of triethylamine, followed by treatment with 10% HCl. Neither Manhas nor Wells discloses the isolation of the cycloaddition product; indeed it is reported later (see Synthesis, September 1975, at p. 557) that the cycloaddition product is the dimeric azetidinone (C). ##STR3##